Among adult leukemias, chronic lymphocytic leukemia (CLL) has the highest rate of new diagnoses per year in the United States. Therapeutic antibodies like the CD20-targeting rituximab have significantly benefited these patients. However, current treatments are not curative and resistance is common. Therapeutic antibodies that target different surface proteins on the cancer cells may help circumvent resistance and are therefore highly desirable. CD37 is a promising alternative target which is highly expressed in CLL. Very little is known about the function of this protein, but its role in promoting survival of certain non-cancerous cells suggests it could function similarly in leukemia to support disease development or progression. A new CD37-targeting antibody- drug conjugate was recently developed to both retain antibody-derived anti-leukemic mechanisms and also deliver anti-proliferative drug to cancer cells. It is hypothesized that this therapeutic could hel eliminate the proliferating subset of CLL cells that is ultimately responsible for a patient's demise. This therapy recently began clinical trials for non-Hodgkins lymphoma and demonstrates promising pre-clinical activity against human CLL in the laboratory and in a mouse model of CLL. In addition to delivering anti-cancer drug to tumor cells, the antibody portion could potentially contribute to efficacy in two ways: directly killing leukemia and promoting elimination of cancer by the immune system. The degree to which these different mechanisms are responsible for its activity in animals is unknown, and this has not been explored for any other antibody-drug conjugate. The objectives of this research are to determine the mechanisms responsible for the efficacy of this therapeutic, investigate potential combination treatments to improve its elimination of tumor cells, and to better understand the functional role of its target (CD37) in leukemia. Aim 1 establishes a mouse model of CLL that lacks CD37, which is used to study this protein's role in malignancy. Aim 2 will elucidate the mechanism of the CD37-targeting antibody-drug conjugate in mouse CLL and evaluate combination therapies predicted to augment its activity. Our long-term goal is to bring effective CD37-targeted therapeutic strategies to the clinic for treatment of CLL and related malignancies. These investigations will address questions that could affect the clinical use of this and other antibody-drug conjugates, in addition to influencing the design of new therapies belonging to this rapidly expanding class of cancer therapeutics. Furthermore, many aspects of the work are relevant to other therapies targeting CD37, several of which are currently being evaluating in clinical trials.